Potassium channel is one of the important ion channels in mammalian, and has been revealed to be involved in maintaining the membrane potential of the excitable cells and the normal physiological functions of histiocytes. Compounds modulating the function of potassium channels can be used in the clinical practice for treating the commonly encountered and multiple cardiovascular diseases such as hypertension, angina diaphragmatic, arrhythmia, congestive heart failure and the like, diabetes, and diseases caused by smooth muscle spasm in bronchia, bladder and ureter.
Potassium channels are mainly classified into two groups: one is voltage-regulated potassium channel, the other is chemical-regulated potassium channel. Each group may be further divided into many subtypes. Using pharmacological methods to study the action properties of novel compounds plays very important roles in elucidating the pharmacological characteristics of potassium channels and their subtypes, as well as in searching for novel and highly effective drugs for clinical therapy.
KATP is one of the chemical-regulated potassium channels. It distributes widely in cardiovascular systems, nerve and glands. Under pathological conditions such as ischemia or anoxia, KATP mediates important pathological or physiological functions. It's an important target for the evaluation of the treatment of hypertension, angina diaphragmatic, arrhythmia, congestive heart failure, diabetes and some diseases caused by smooth muscle spasm in bronchi, bladder and ureter.
Drugs modulating potassium channels are termed as potassium channel openers (PCO) or potassium channel activators (KCA). They are classified into three types based on their physiological activities. Type-1 directly acts on transition sub-units independent of both ATP and nucleoside diphosphate (NDP), including pinacidil, levcromakalim, YM-934 and aprikalim, etc.; type-2 acts on sites which inhibit ATP binding or related sites thereof, and is dependent on ATP, including ER-001533, HOE234, etc.; type-3 acts on NDP binding sites and is dependent on NDP, such as nicorandil. Based on chemical structure, they may fall into the following groups: substituted cyanoguanidines or thioureas (e.g. pinacidil, ER-001533, U-94968, BRL-49074, etc.), substituted arylamides and derivatives thereof (e.g. nicorandil, KRN-239, Ki-1769, etc.), substituted benzopyranes and modifications thereof (e.g. levcromakalim, YM-934, Ro-31-6930, SDZ-PCO-400, UR8225, etc.), substituted cycloalkylthioformamides (e.g. aprikalim, etc.), substituted tertiary alcohols, dihydropyridines and their modifications, benzothiadiazines, pyrimidines and other heterocycles. Till now, there is no reports that secondary amines can modulate potassium channels. The antagonists of KATP are sulfonylureas such as glyburide and gludipizide. They can antagonize the cardiovascular activities of KCAs. The major drawback of the reported KCAs is lack of tissue specificity and has severe side-effects such as reflex tachycardia, edema, cardialgia, flush and cardiomegalia, etc. Therefore, it is important to discover new medicament with higher tissue specificity.